Project Summary/Abstract Fatigue interference with activities, mood, and cognition is one of the most prevalent and distressing concerns of advanced gastrointestinal (GI) cancer patients. As fatigue interferes with patient functioning, family caregivers often report feeling burdened by increasing responsibilities. Evidence-based interventions addressing cancer patient fatigue interference and caregiver burden are lacking. In pilot studies, Acceptance and Commitment Therapy (ACT) has shown potential for reducing symptom-related suffering in cancer patients. We recently conducted a pilot study in metastatic breast cancer that tested a novel ACT intervention combining acceptance and mindfulness exercises (e.g., meditations, performing activities with greater awareness) with identification of personal values and engagement in activities consistent with these values. This telephone-based intervention showed strong evidence of feasibility, acceptability, and promise for reducing fatigue interference with activities, mood, and cognition. The proposed pilot study builds upon this patient-focused work to test a novel, dyadic ACT intervention for both advanced GI cancer patients with moderate-severe fatigue interference and their family caregivers with significant caregiving burden. In this trial, 40 patient-caregiver dyads will be randomly assigned in equal numbers to either the ACT intervention or an education/support control condition. Dyads in both conditions will attend six weekly 50-minute telephone sessions. Outcomes will be assessed at baseline, 2 weeks post-intervention, and 3 months post-intervention. We will evaluate the feasibility, acceptability, and preliminary efficacy of ACT on improving patient fatigue interference and caregiver burden. Secondary outcomes include patient sleep interference and patient and caregiver engagement in daily activities, psychological flexibility, and quality of life. We will also explore the effects of ACT on patient and caregiver physical and mental health service use. Study findings will inform an R01 application to conduct a large-scale trial of intervention efficacy. Results will also provide a foundation for a program of research focused on the novel application of ACT to symptom interference with functioning and caregiver burden in advanced cancer.